According to a patient survey conducted by the Japanese Ministry of Health, Labor and Welfare in Heisei 14 (2002), the total number of diabetes patients in Japan was 2.28 million. Moreover, according to a diabetes survey conducted in the same year, the total number of people “strongly suspected of having diabetes” and people in whom “the possibility of diabetes cannot be denied” had increased to 16.20 million, and this increase has been perceived as a problem.
Since the insulin secretory capacity of Japanese is low due to genetic factors, the Japanese domestic market is mainly for impaired insulin secretion. However, due to the westernization of Japanese dietary habits, the number of patients with insulin resistance is gradually increasing in recent years. Accordingly, there is a demand for drugs that are expected to be effective for both impaired insulin secretion and insulin resistance.
Glucokinase (GK), which catalyzes the phosphorylation of glucose, functions as a glucose sensor in the body and increases glucose utilization in the liver and the secretion of insulin in a high glucose state. In diabetes patients, the homeostasis of glucose concentration in the body is not maintained in a normal state. Therefore, by activating GK, insulin secretion from the pancreas, which depends on the concentration of glucose, is facilitated. In the lever, the activation of GK increases the glucose utilization and suppresses glucose output. This dual action reduces the blood glucose level (Non-Patent Documents 1 to 3). Therefore, it is desirable to provide GK activators useful as diabetes drugs that are effective for both impaired insulin secretion (action in the pancreas) and insulin resistance (action in the liver).
Various amide compounds are known as GK activators. Examples of such amide compounds include: aryl cycloalkyl propionamides (Patent Document 1); 2,3-di-substituted trans olefinic N-heteroaromatic or ureido propionamides (Patent Document 2); alkynyl phenyl heteroaromatic amides (Patent Document 3); hydantoins (Patent Document 4); substituted phenylacetamides (Patent Document 5); para-alkyl, aryl, cycloheteroalkyl or heteroaryl (carbonyl or sulfonyl) amino substituted phenyl amides (Patent Document 6); alpha-acyl and alpha-heteroatom-substituted benzene acetamides (Patent Document 7); tetrazolyl-phenyl acetamides (Patent Document 8); fused heteroaromatic compounds (Patent Document 9); phenylacetamides having a cycloalkane with a single carbon atom substituted or a heterocycle (Patent Document 10); and other amide compounds (Patent Documents 11 to 21). However, these patent documents do not disclose acrylamide compounds in which two fluorine atoms are attached to different carbon atoms of a cyclopentyl group.